Circadian rhythm

Based on Wikipedia: Circadian rhythm

The Clock That Runs Without Winding

In 1729, a French astronomer named Jean-Jacques d'Ortous de Mairan locked a mimosa plant in a dark closet and waited. The plant, famous for folding its leaves at night and opening them at dawn, should have been confused. With no sunlight to guide it, how would it know when to sleep?

It knew anyway.

Day after day, in complete darkness, the mimosa continued its rhythmic dance—leaves unfurling at the usual morning hour, closing again as evening approached. Something inside the plant was keeping time, and that something didn't need the sun to do it.

This was humanity's first glimpse of what scientists would later call the circadian rhythm—from the Latin circa (around) and dies (day). It's an internal clock that ticks away in nearly every living thing on Earth, from the simplest bacteria to the most complex human brain. And unlike the clocks on our walls, this one runs on chemistry, not gears.

A Very Old Invention

The circadian rhythm isn't just old. It's ancient in a way that's hard to fathom.

Scientists believe these internal clocks evolved independently at least four separate times—in animals, plants, fungi, and cyanobacteria. When the same solution evolves multiple times in unrelated organisms, biologists call it convergent evolution, and it's a strong signal that the solution is extraordinarily useful. Eyes evolved independently dozens of times. Flight evolved in insects, birds, bats, and pterosaurs. And the 24-hour internal clock? It emerged again and again, across the tree of life.

Why would keeping time matter so much?

The answer might lie in a catastrophe that happened about 2.3 billion years ago: the Great Oxidation Event. Before that time, Earth's atmosphere contained almost no oxygen. Then cyanobacteria—tiny photosynthetic organisms—began pumping oxygen into the air as a waste product of their metabolism. For most life on Earth at the time, this was apocalyptic. Oxygen is corrosive. It reacts violently with organic molecules. It kills.

But oxygen levels aren't constant throughout the day. Sunlight drives photosynthesis, which produces oxygen and reactive oxygen species—molecules that can damage DNA and proteins. An organism that could anticipate the daily rise and fall of these dangerous chemicals would have a survival advantage. It could prepare its defenses before the assault began.

So the circadian clock may have evolved not to track the sun directly, but to predict the daily chemical warfare that sunlight brings.

How the Clock Works

For decades, scientists assumed that circadian rhythms required a brain, or at least something like a nervous system, to coordinate them. They were wrong.

The simplest known circadian clock belongs to a cyanobacterium called Synechococcus elongatus. This single-celled organism has no brain, no nervous system, no organs of any kind. Yet it keeps perfect time.

In 2005, researchers demonstrated something remarkable: they could recreate this bacterial clock in a test tube using just three proteins, named KaiA, KaiB, and KaiC. Add these proteins to a solution with ATP—the energy molecule that powers all cellular work—and the mixture will oscillate with a 22-hour rhythm for days on end. No living cell required. No DNA being read and transcribed. Just three proteins, cycling through their chemical states like the gears of a watch.

This is astonishing. It means that the most basic circadian clock is not a biological process in the usual sense. It's pure chemistry—a self-sustaining chemical oscillation that happens to take about 24 hours to complete.

In more complex organisms, the clock becomes more elaborate. In fruit flies—the workhorses of circadian research—a gene called period plays a central role. The protein it produces accumulates in cells during the day, eventually reaching levels high enough to shut down its own production. Then the protein slowly degrades overnight, and the cycle begins again.

This is called a feedback loop. Imagine a thermostat that turns off the heater when the room gets warm enough, then turns it back on when the room cools. The circadian clock works similarly, but instead of temperature, it's tracking its own protein levels.

The Discovery of Clock Genes

The period gene was discovered in 1971 by two scientists named Ron Konopka and Seymour Benzer, who were studying fruit flies at the California Institute of Technology. They created mutant flies and watched their behavior, looking for any that had unusual daily rhythms.

They found three types.

One group of mutants had internal clocks that ran too fast, completing their daily cycle in about 19 hours instead of 24. Another group ran too slow, taking 28 hours per cycle. And a third group had no rhythm at all—their behavior was completely random with respect to time of day.

All three mutations were in the same gene. Konopka and Benzer had found the first genetic component of the biological clock.

It took another thirteen years for scientists to isolate the actual gene and figure out what it did. The work was done by two competing teams—one led by Jeffrey Hall and Michael Rosbash at Brandeis University, the other by Michael Young at Rockefeller University. They discovered that the period gene produces a protein that accumulates in cells during the night, peaks around dawn, and then declines throughout the day. This protein directly regulates its own production, creating the feedback loop that drives the 24-hour cycle.

In 2017, Hall, Rosbash, and Young received the Nobel Prize in Physiology or Medicine for this work. By that point, they and others had discovered an entire network of clock genes that interact in complex ways, fine-tuning the body's sense of time with remarkable precision.

Setting Your Clock

An internal clock is only useful if it matches the external world. A clock that runs at 24 hours and 15 minutes would drift further and further from true solar time, eventually being completely out of sync.

This is where zeitgebers come in—a German word meaning "time givers." These are external signals that reset the internal clock each day, keeping it synchronized with the environment.

Light is the most powerful zeitgeber. When light enters your eyes, specialized cells in your retina—different from the ones that let you see—send signals directly to a tiny region of the brain called the suprachiasmatic nucleus, or SCN. This structure, containing only about 20,000 neurons, is the master clock of the human body. It receives the light signal and uses it to calibrate the rest of your biological rhythms.

But here's something curious: you don't need to be able to see to have your clock set by light.

Completely blind people—even those who have no conscious perception of light whatsoever—can still have their circadian rhythms entrained by bright light, as long as their retinas are intact. The light-sensing cells that set the clock are separate from the cells that create vision. They respond to light even when the visual system is completely dark.

Temperature can also serve as a zeitgeber, as can meal timing and social cues. In laboratory experiments, people isolated from all external time cues will naturally drift to their own internal rhythm—which, for most people, runs slightly longer than 24 hours. This explains why, when left to your own devices on a long vacation with no schedule, you might find yourself going to bed later and later each night.

Temperature Compensation: The Unsolved Puzzle

Most chemical reactions speed up when you heat them and slow down when you cool them. This is basic chemistry—molecules move faster at higher temperatures, so they collide and react more frequently. The rule of thumb is that for every 10-degree Celsius increase in temperature, reaction rates roughly double.

This creates a problem for any clock based on chemical reactions. If your circadian rhythm sped up in summer and slowed down in winter, it would be useless for tracking real time.

Yet circadian rhythms maintain their approximately 24-hour period across a wide range of temperatures. A fruit fly in a warm room has the same circadian period as one in a cool room. A lizard basking on a hot rock keeps the same time as one hiding in the shade.

This is called temperature compensation, and scientists still don't fully understand how it works. Somehow, the clock mechanism includes built-in corrections that counteract the normal temperature-dependence of chemical reactions. It's as if the clock has its own internal thermostat, speeding up some reactions and slowing down others to maintain the same overall period.

This is one of three defining characteristics that distinguish a true circadian rhythm from a simple response to external cues. The rhythm must persist in constant conditions (like de Mairan's mimosa in the dark closet). It must be able to be reset by zeitgebers. And it must maintain its period regardless of temperature.

Ancient Observations

Jean-Jacques de Mairan was not the first person to notice that living things keep their own time. He was simply the first to design an experiment to prove it.

The earliest written observation of circadian behavior comes from Theophrastus, a Greek philosopher who lived in the 4th century BC. He described a tree with "many leaves like the rose, that closes at night, but opens at sunrise, and by noon is completely unfolded; and at evening again it closes by degrees and remains shut at night." The natives, he wrote, said that "it goes to sleep."

Theophrastus got this information secondhand, from a ship's captain named Androsthenes who served under Alexander the Great. Centuries later, botanists identified the tree as the tamarind.

Chinese medical texts from around the 13th century also reference daily biological rhythms, including manuals for acupuncture that specified different treatment points for different times of day. The physicians of that era may not have understood the mechanism, but they recognized that the body was not the same at midnight as it was at noon.

When Clocks Go Wrong

Jet lag is the most common circadian disorder, and nearly everyone has experienced it. When you fly across multiple time zones, your internal clock remains set to your home time even as the sun rises and sets on a completely different schedule. The result is that peculiar, muzzy-headed state where you're exhausted at dinner time and wide awake at 3 AM.

Given a few days, your clock will reset itself, entrained by the new pattern of light and darkness. But some people have more serious circadian problems.

In 1999, researchers studying a family in Utah discovered something unusual. Multiple family members were what sleep scientists call "extreme morning larks"—people who naturally fall asleep around 7:30 PM and wake up around 4:30 AM. This wasn't a lifestyle choice. It was inherited.

The researchers traced the trait to a mutation in a gene called PER2, the human version of the fruit fly's period gene. A single change—one amino acid swapped for another in a protein made of hundreds—shifted their entire daily rhythm forward by about four hours. This condition is now called Familial Advanced Sleep Phase Syndrome, or FASPS.

There are also people with the opposite problem: Delayed Sleep Phase Syndrome, where the internal clock runs late and resists all attempts to reset it. These individuals may not feel sleepy until 4 AM and cannot easily wake before noon, regardless of alarms or willpower. This is not laziness. It's biology.

Clocks Throughout the Body

For a long time, scientists thought of the circadian system as centralized—a master clock in the brain directing everything else. We now know this is an oversimplification.

Nearly every cell in your body has its own clock. Your liver cells keep time. Your fat cells keep time. Your skin cells keep time. These peripheral clocks are synchronized by signals from the master clock in the suprachiasmatic nucleus, but they can also be influenced by local cues like meal timing.

This creates interesting possibilities for clocks to become desynchronized. If you eat at unusual hours—as shift workers often must—your liver clock may drift out of phase with your brain clock. Your pancreas might be expecting to process food at one time while your brain is expecting sleep. This internal misalignment may explain some of the health problems associated with shift work, including increased rates of obesity, diabetes, and cardiovascular disease.

Mice with mutations in their clock genes become obese and develop metabolic problems resembling diabetes. Deleting a gene called Rev-ErbA alpha changes how mice balance glucose and fat metabolism, predisposing them to diet-induced obesity. Whether similar genetic variations in humans contribute to metabolic disease is still being investigated.

Creatures of the Dark

What happens when an animal never sees the sun at all?

The blind mole rat, Spalax, lives its entire life underground in total darkness. It has no functional eyes—just small, vestigial organs covered by skin. Yet it maintains a circadian rhythm.

How? The mole rat still has photoreceptors—light-sensing cells—even though it cannot see. These cells are sufficient to detect light when the animal occasionally surfaces. But even in the complete absence of light, the internal clock keeps running, synchronized by other cues we don't fully understand.

Laboratory animals kept in constant darkness for extended periods will "free-run"—their clocks continue to oscillate, but without zeitgebers to reset them, they gradually drift. If an animal's internal period is 24 hours and 20 minutes, its sleep cycle will shift later by 20 minutes each day, eventually cycling through all hours of the day and night.

Astronauts face a version of this problem. In orbit, the sun rises and sets every 90 minutes as the spacecraft circles the Earth, completely overwhelming the normal 24-hour light-dark cycle. Early space missions found that crew members' circadian rhythms became disrupted, affecting their sleep, alertness, and performance.

Modern spacecraft now include lighting systems designed to mimic the natural day-night cycle, providing bright blue-enriched light during "daytime" hours and dimmer, warmer light in the evening. This artificial zeitgeber helps keep astronauts' clocks synchronized, improving both their sleep and their ability to function during critical mission activities.

Beyond the Clock: Seasonal Time

The circadian system does more than track the hours. It also measures something larger: the changing length of the day.

This is called photoperiodism, and it's how many organisms know what season it is. As winter approaches in the Northern Hemisphere, days grow shorter. As summer nears, they lengthen. By measuring how long the light period lasts relative to the dark period, organisms can predict upcoming seasonal changes with remarkable accuracy.

For many animals, this information is critical. Birds need to know when to migrate. Bears need to know when to hibernate. Deer need to know when to breed so that their fawns are born in spring, when food is abundant and temperatures are mild.

Plants use photoperiodism too. Many species flower only when the day length crosses a particular threshold, ensuring that they bloom at the right time of year for pollination and seed development.

The circadian clock is intimately involved in measuring day length, though the exact mechanism varies across species. In some cases, it seems to create a "photosensitive window"—a particular time of day when the organism is sensitive to light. If light falls during this window, the organism interprets it as a long day; if darkness falls during this window, it interprets the day as short.

The Future of Circadian Science

Understanding circadian rhythms has practical implications far beyond treating jet lag. Chronotherapy—timing medical treatments to match the body's natural rhythms—is a growing field. Some cancer chemotherapy drugs, for instance, are more effective and less toxic when given at particular times of day, because cancer cells and healthy cells may be on different schedules.

Light therapy is now an established treatment for certain types of depression, particularly seasonal affective disorder. Carefully timed exposure to bright light can shift the circadian clock, alleviating symptoms in many patients.

And as we spend more of our lives under artificial lighting, staring at screens that emit the same blue wavelengths that reset our clocks, understanding how light affects our biology becomes increasingly urgent. The modern epidemic of sleep problems may be, in part, a circadian disorder—our clocks confused by a world that never truly gets dark.

The mimosa plant in de Mairan's closet, folding and unfolding its leaves in the darkness, was demonstrating something profound: life doesn't just respond to the world. It anticipates it. And that anticipation—the ability to know what's coming before it arrives—may be one of the most ancient and essential features of being alive.